6-(acylaminoaryl)-3(2H)-pyridazinone derivatives and their use

ABSTRACT

Novel 6-(acylaminoaryl)-3(2H)-pyridazinones of the formula ##STR1## where R 1 , R 2 , R 3 , R 4 , A and B have the meanings given in the description, and their preparation are described and inhibiting thrombocyte aggregation and gastric secretion. 
     The compounds are useful for treating disorders.

The present invention relates to novel6-(acylaminoaryl)-3(2H)-pyridazinone derivatives, processes for theirpreparation and their use in the treatment of disorders.

Pharmacologically active 6(acylamino)-4,5-dihydro-3(2H)-pyridazinoneshave been disclosed, cf. German Laid-Open Applications DOS 1,670,158,DOS 2,123,246, DOS 2,150,436, DOS 2,157,453, DOS 2,304,977, DOS2,727,481, DOS 2,854,191, DOS 2,845,475, DOS 3,022,176, DOS 3,022,177,DOS 3,033,702, DOS 3,209,158 and DOS 3,209,159, and Japanese PreliminaryPublished Applications 53/124,279, 58/008,015 and 58/008,016, and thepreviously unpublished Patents WO 83/01,447 and U.S. Pat. No. 4,397,854.6-(Acylaminoaryl)-3(2H)-pyridazinones having pharmacological activityhave also been disclosed, cf. Japanese Preliminary PublishedApplications 58/008,015 and 58/008,016, U.S. Pat. No. 4,397,854, and J.Med. Chem. 17 (1974), 273-281.

The substances described in these publications possess antihypertensive,anti-inflammatory, membrane-stabilizing, thrombocyteaggregation-inhibiting, cardiotonic and/or coronary dilator properties,or have a cardiovascular or antiallergic action.

We have found that 6-(acylaminoaryl)-3(2H)-pyridazinone derivatives ofthe formula I ##STR2## where the substituents on the phenylene radicalare meta or para to one another, A and B are each hydrogen or togetherform a bond, R¹ and R² are each hydrogen or C₁ -C₃ -alkyl, or, where Aand B are hydrogen, together form a C₁ -C₄ -alkylene radical, R³ isstraight-chain C₁ -C₄ alkylene which can be substituted by 1 or 2 C₁ -C₅-alkyl groups, and R⁴ is

(a) pyrrol-1-yl, imidazol-1-yl, pyrazol-1-yl or 1,2,4-triazol-1-yl, or

(b) a group of the formula II ##STR3## where the broken line can be anadditional bond, R⁵ and R⁶ are identical or different and are eachhydrogen, a C₁ -C₄ -hydrocarbon radical which is unsubstituted orsubstituted by C₃ -C₈ -cycloalkyl or by phenyl which is unsubstituted orsubstituted by 1 to 3 C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, trifluoromethyland/or nitro groups and/or halogen atoms, or are each C₃ -C₈-cycloalkyl, hydroxyl, trifluoromethyl, C₁ -C₄ -acyl, carboxyl, (C₁ -C₅-alkoxy)-carbonyl or cyano, or are each C₆ -C₁₀ -aryl which isunsubstituted or mono-substituted, disubstituted or trisubstituted byhalogen, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, hydroxyl, trifluoromethyl, C₁-C₄ -acyl, carboxyl, (C₁ -C₅ -alkoxy)-carbonyl, cyano, nitro, amino, C₁-C₄ -alkylamino, di-C₁ -C₄ -alkylamino, anilino, or C₁ -C₄ -acylamino,or are each a 5-membered or 6-membered hetaryl radical which contains 1to 3 hetero atoms and may or may not be benzofused, or are each a groupof the formula R⁷ R⁸ N--, where R⁷ and R⁸ are identical or different andare each hydrogen, C₁ -C₈ -alkyl which is unsubstituted or substitutedby phenyl which is unsubstituted or substituted by 1 to 3 C₁ -C₄ -alkyl,C₁ -C₄ -alkoxy, trifluoromethyl and/or nitro groups and/or halogenatoms, or are each phenyl which can be monosubstituted, disubstituted ortrisubstituted by halogen, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy,trifluoromethyl, C₁ -C₄ -acyl, carboxyl, (C₁ -C₅ -alkoxy)-carbonyl,cyano and/or nitro, or are each C₁ -C₈ -acyl or C₆ -C₁₀ -aroyl, and thearoyl group can be monosubstituted, disubstituted or trisubstituted byhalogen, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, hydroxyl, trifluoromethyl, C₁-C₄ -alkylthio, C₁ -C₄ -alkylsulfoxyl, C₁ -C₄ -alkylsulfonyl, C₁ -C₄-acyl, carboxyl, (C₁ -C₅ -alkoxy)-carbonyl, cyano, nitro, amino, C₁ -C₄-alkylamino, di-C₁ -C₄ -alkylamino or C₁ -C₄ -acylamino, or the group R⁷R⁸ N-- is a benzimidazol-2-on-1-yl radical, or R⁵ and R⁶ together form aC₁ -C₄ -alkylene chain, the bicyclic structure being unsubstituted orsubstituted by 1 to 3 C₁ -C₃ -alkyl groups, and m is 0, 1, 2 or 3, or

(c) a group of the formula III ##STR4## where R⁹ is a C₁ -C₁₄-hydrocarbon radical which is unsubstituted or substituted by hydroxyl,C₃ -C₈ -cycloalkyl (in which case a C₅ -C₈ -cycloalkyl group can bebenzofused) or C₆ -C₁₀ -aryl which can contain 1 to 3 C₁ -C₄ -alkyl, C₁-C₄ -alkoxy, trifluoromethyl, nitro, hydroxyl, C₁ -C₄ -acyl, carboxyl,(C₁ -C₅ -alkoxy)-carbonyl, amido, N-(C₁ -C₄ -alkyl)-amido, N,N-di-(C₁-C₄ -alkyl)-amido, tri(C₁ -C₄ -alkyl)-silyl, cyano, amino, C₁ -C₄-alkylamino, di-(C₁ -C₄ -alkyl)-amino, C₁ -C₄ -acylamino groups and/orhalogen atoms; a C₆ -C₁₀ -aroyl group which is unsubstituted orsubstituted by 1 to 3 C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, trifluoromethyl,nitro, hydroxyl, C₁ -C₄ -acyl, carboxyl, C₁ -C₅ -alkoxycarbonyl,N,N-di-(C₁ -C₄ -alkyl)-amido, cyano, di-(C₁ -C₄ -alkyl)-amino groupsand/or halogen atoms; or a hetaroyl group having 5 or 6 ring members,which can contain 1 to 3 hetero atoms and may be benzofused; a C₃ -C₁₂-cycloalkyl, C₁ -C₈ -acyl or (C₁ -C₅ -alkoxy)-carbonyl group or a C₆-C₁₀ -aryl radical which is unsubstituted or monosubstituted,disubstituted or trisubstituted by halogen, C₁ -C₄ -alkyl, C₁ -C₄-alkoxy, hydroxyl, trifluoromethyl, C₁ -C₄ -acyl, carboxyl, (C₁ -C₅-alkoxy)-carbonyl, cyano, nitro, amino, C₁ -C₄ -alkylamino, di-C₁ -C₄-alkylamino, arylamino or C₁ -C₄ -acylamino; or a 5-membered or6-membered hetaryl radical which may be benzofused, contains 1 to 3nitrogen atoms and may or may not contain an oxygen atom or a sulfuratom, and p is 2 or 3, or

(d) a group of the formula IV

    --NR.sup.10 R.sup.11                                       (IV)

where

R¹⁰ and R¹¹ are each hydrogen or a C₁ -C₁₂ -hydrocarbon radical which isunsubstituted or substituted by one or two phenyl radicals, which maypossess 1 to 3 C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, trifluoromethyl and/ornitro groups and/or halogen atoms, or by naphthyl, C₃ -C₈ -cycloalkylwhich can contain 1 to 3 C₁ -C₄ -alkyl groups (in which case C₅ -C₈-cycloalkyl groups can be benzofused), or a C₇ -C₁₀ -bicycloalkyl groupwhich can contain 1 to 3 C₁ -C₄ -alkyl groups;

C₃ -C₁₂ -cycloalkyl which can be substituted by 1 to 3 C₁ -C₄-hydrocarbon radicals which can contain a phenyl group (which can bemonosubstituted, disubstituted or trisubstituted by C₁ -C₄ -alkyl, C₁-C₄ -alkoxy, trifluoromethyl, nitrile, nitro and/or halogen) or a C₃ -C₆-cycloalkyl group, or by a phenyl group (which can contain 1 to 3 C₁ -C₄-alkyl, C₁ -C₄ -alkoxy, trifluoromethyl, nitrile or nitro groups and/orhalogen atoms) or a C₃ -C₈ -cycloalkyl group; a bicyclic or tricyclic C₇-C₁₀ -alkyl radical which can be substituted by 1 to 3 C₁ -C₄ -alkylgroups, or a benzofused C₅ -C₇ -cycloalkyl group, or

(e) a group of the formula V ##STR5## where R¹² and R¹³ are eachhydrogen, halogen, C₁ -C₄ -alkyl or C₁ -C₄ -alkoxy, and n is 1, 2 or 3,or

(f) a group of the formula VI ##STR6## where G is oxygen or sulfur, andR¹⁴ and R¹⁵ are each hydrogen or C₁ -C₄ -alkyl, with the proviso that ifR¹, R², A and B are each hydrogen, and the acylamino group is in thepara position on the phenyl ring in I, R³ must not be an unsubstitutedor C₁ -C₅ -alkyl-substituted methylene group, and if R², A and B areeach hydrogen, R¹ is hydrogen or C₁ -C₃ -alkyl and R³ is unsubstitutedor C₁ -C₄ -alkyl-substituted methylene, then R⁴ must not be a group ofthe formula V where R¹⁰ and R¹¹ are each hydrogen or unsubstituted C₁-C₄ -alkyl, and their salts with physiologically tolerated acids haveuseful pharmacological properties.

The substituents on the phenyl ring are preferably in the para position.

Preferably, R¹ and R² are each hydrogen or methyl, or together form aC₁ - or C₂ -alkylene radical. R¹ is particularly preferably hydrogen or,where A and B are each hydrogen, methyl. R² is particularly preferablyhydrogen or, where A and B together constitute a bond, methyl.

If R₁ and R₂ together form a C₁ -C₄ -alkylene group, this is veryparticularly preferably methylene.

Preferably, A and B are each hydrogen or together constitute a bond, butthey are particularly preferably hydrogen.

R³ is preferably a straight-chain C₁ -C₄ -alkylene group which can besubstituted by a C₁ -C₃ -alkyl or by two methyl groups. R³ isparticularly preferably a C₁ -C₃ -alkylene group, in particularmethylene or ethylene, which can be substituted by methyl.

Among the radicals R⁴ stated under (a), the 1-imidazol-1-yl radical ispreferred.

If R⁴ is a group of the formula II, R⁵ is preferably hydrogen or C₁ -C₄-alkyl which is unsubstituted or substituted by phenyl, or C₃ -C₆-cycloalkyl, or phenyl which can be unsubstituted or substituted by 1 or2 halogen atoms, C₁ -C₄ -alkyl groups, C₁ -C₄ -alkoxy groups and/or atrifluoromethyl, nitrile and/or nitro group, or is preferably a group ofthe formula R⁷ R⁸ N--, where R⁷ is hydrogen or phenyl which can bemonosubstituted or disubstituted by halogen atoms, C₁ -C₄ -alkyl groups,C₁ -C₄ -alkoxy groups and/or a nitrile and/or nitro group, and R⁸ is C₁-C₄ -acyl or benzoyl, or R⁷ and R⁸, together with the nitrogen atom,form a benzimidazol-2-on-1-yl group.

R⁶ is preferably hydrogen, C₁ -C₄ -alkyl, hydroxyl, C₁ -C₄ -acyl, (C₁-C₅ -alkoxy)-carbonyl or cyano.

R⁵ is particularly preferably phenyl-substituted C₁ -C₄ -alkyl,unsubstituted or halogen-substituted phenyl, or a group of the formulaR⁷ R⁸ N, where R⁷ is phenyl and R⁸ is C₁ -C₄ -acyl. Among theseradicals, benzyl and unsubstituted or halogen-substituted phenyl areparticularly noteworthy.

If R⁵ and R⁶ together form a C₁ -C₄ -alkylene chain, chains which areunsubstituted or substituted by 1 to 3 methyl groups are preferred.

m is preferably 0, 1 or 2, particularly preferably 1.

If R⁴ is a group of the formula III, R⁹ is preferably one of thefollowing radicals: a C₁ -C₃ -hydrocarbon radical which can besubstituted by naphthyl or by phenyl which is unsubstituted ormonosubstituted or disubstituted by halogen, C₁ -C₄ -alkyl or C₁ -C₄-alkoxy and/or a trifluoromethyl, hydroxyl, C₁ -C₄ -acyl, (C₁ -C₅-alkoxy)-carbonyl, nitro and/or nitrile group; naphthyl; phenyl whichmay be monosubstituted, disubstituted or trisubstituted by halogen, C₁-C₄ -alkyl or C₁ -C₄ -alkoxy and/or by a trifluoromethyl or C₁ -C₄ -acylgroup; or a 6-membered hetaryl radical containing 1 or 2 nitrogen atoms.

R⁹ is particularly preferably a C₁ -C₃ -hydrocarbon radical which issubstituted by phenyl which is unsubstituted or C₁ -C₄-alkoxy-substituted; naphthyl; phenyl which can be substituted by 1 or 2halogen atoms, C₁ -C₄ -alkyl groups or C₁ -C₄ -alkoxy groups and/or atrifluoromethyl group; or pyridyl. Benzyl which can be substituted bymethoxy, phenyl which can be substituted by halogen, and pyridyl areparticularly important.

p is preferably 2.

If R⁴ is a group of the formula IV, R¹⁰ preferably has one of thefollowing meanings:

C₁ -C₈ -alkyl which is unsubstituted or substituted by phenyl which cancontain 1 or 2 C₁ -C₄ -alkyl groups and/or halogen atoms; C₃ -C₁₂-cycloalkyl which can be substituted by 1 to 3 methyl groups, a benzylradical or a phenyl radical; a bicyclic or tricyclic C₇ -C₁₀ -alkylradical which is unsubstituted or substituted by 1 to 3 methyl radicals;or a benzofused C₅ -C₇ -cycloalkyl group.

R¹⁰ particularly preferably has one of the following meanings: C₁ -C₄-alkyl which is substituted by phenyl; C₆ -C₈ -cycloalkyl which can besubstituted by phenyl; or a benzofused C₅ -C₆ -cycloalkyl group.

R¹¹ is preferably hydrogen or C₁ -C₈ -alkyl, in particular hydrogen orC₁ -C₄ -alkyl.

If R⁴ is a group of the formula V, R¹² and R¹³ are each preferablyhydrogen, halogen or C₁ -C₄ -alkyl, and n is 1 or 2. R¹² and R¹³ areeach particularly preferably hydrogen, and n is particularly preferably2.

If R⁴ is a group of the formula VI, G is preferably oxygen or sulfur,and R¹⁴ and R¹⁵ are each preferably hydrogen or methyl.

R⁴ is preferably a group of the formula II, III, IV or V, particularlypreferably a group of the formula II, III or V.

The compounds of the formula I in which A, B and R² are each hydrogenare 6-aryl-4,5-dihydro-3(2H)-pyridazinones, while compounds of theformula I in which A and B are each hydrogen and R¹ and R² together forma methylene, ethylene, propylene or butylene group are2-aryl-3,4-diazabicyclo[4.1.0]hept-2-en-5-ones,2-aryl-3,4-diazabicyclo[4.2.0]oct-2-en-5-ones,2-aryl-3,4-diazabicyclo[4.3.0]non-2-en-5-ones or2-aryl-3,4-diazabicyclo[4.4.0]dec-2-en-5-ones.

Compounds of the formula I in which A and B together constitute a bondare 6-aryl-3(2H)-pyridazinones.

Examples of suitable physiologically tolerated acids are hydrochloricacid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaricacid, malonic acid, succinic acid, maleic acid, fumaric acid, malicacid, lactic acid, diamidosulfonic acid, glutamic acid and asparticacid.

The novel compounds of the formula I and their salts withphysiologically tolerated acids can be prepared by a method in which

(a) a compound of the formula VII ##STR7## where the substituents on thephenylene radical are para or meta to one another, X is halogen and A,B, R¹, R² and R³ have the stated meanings, is reacted with a compound ofthe formula VIII

    R.sup.4 --H                                                (VIII)

where R⁴ has the stated meanings, or

(b) an aminophenylpyridazinone of the formula IX ##STR8## where the NH₂group is in the para or meta position, and A, B, R¹ and R² have thestated meanings, is acylated with a compound of the formula X

    R.sup.4 --R.sup.3 --CO--Y.HY                               (X)

where R³ and R⁴ have the stated meanings and Y is chlorine or bromine,or

(c) a ketocarboxylic acid of the formula XI ##STR9## where A, B, R¹, R²,R³ and R⁴ have the stated meanings, and the acylamino group is in thepara or meta position, is cyclized with hydrazine, or

(d) where A and B together constitute a bond and R² is methyl, adihydropyridazinone of the formula I ##STR10## where R¹, R³ and R⁴ havethe stated meanings, and A, B and R² are each hydrogen, is reacted withformaldehyde, and the resulting compound is, if desired, converted toits salts with physiologically tolerated acids.

Reaction (a) is carried out under conventional conditions, ie. as a ruleusing not less than an equimolar amount of the compound of the formulaVIII in the presence of not less than an equimolar amount of a base asan acid acceptor, with or without the addition of an iodide as acatalyst if X is not iodine, advantageously in the presence of asolvent, at from 0° to 140° C., preferably from 30° to 100° C., ifappropriate at the boiling point of the reaction mixture, and underatmospheric or superatmospheric pressure. It is also possible todispense with the addition of a base, in which case it is advantageousto use not less than two equivalents of the compound of the formulaVIII.

Suitable solvents are those which are inert under the reactionconditions, such as aromatic hydrocarbons, eg. toluene or xylene,aliphatic or aromatic hydrocarbons, eg. methylene chloride, ethylenechloride or chlorobenzene, cyclic aliphatic ethers, eg. tetrahydrofuranor dioxane, lower alkanols, eg. methanol, ethanol or isopropanol,aliphatic ketones, eg. acetone, diethyl ketone or methyl ethyl ketone,or dialkylamides, eg. dimethylformamide or N-methylpyrrolidone. Basesused as acid acceptors are advantageously inorganic bases, eg. sodiumcarbonate, potassium carbonate, sodium bicarbonate or potassiumbicarbonate, tertiary organic amines, eg. triethylamine, or an excess ofthe amine R⁴ H.

Iodides used as catalysts are advantageously alkali metal iodides,preferably potassium iodide or sodium iodide, or quaternary ammoniumiodides, eg. tetrabutylammonium iodide. The iodide is used as a rule inan amount of from 1 to 10 mole %. However, it is also possible to employas much as a molar amount of the catalyst.

The substances of the formula VII which are used as starting compoundsare known, or can be prepared by a conventional method.

Reaction (b) takes place under conditions conventionally used forN-acylation, as a rule using not less than an equimolar amount of theacid halide, advantageously in the presence of a solvent, in thepresence or absence of an acid acceptor, at from 0° to 100° C.,preferably at no higher than 70° C., if appropriate at the boiling pointof the reaction mixture, and under atmospheric or superatmosphericpressure.

Solvents preferably used on an industrial scale are ketones, eg.acetone, diethyl ketone or methyl ethyl ketone; otherwise, preferredsolvents are, for example, aromatic hydrocarbons, such as benzene,toluene or xylene, cyclic ethers, such as tetrahydrofuran or dioxane,aliphatic or aromatic chlorohydrocarbons, such as methylene chloride,ethylene chloride or chlorobenzene, or dialkylamides, such asdimethylformamide or N-methylpyrrolidone. Acid acceptors areadvantageously weak inorganic bases, eg. sodium carbonate, potassiumcarbonate, sodium bicarbonate or potassium bicarbonate, or organicbases, eg. tertiary amines.

The substances of the formula IX which are used as starting compoundsare known, or can be prepared by a conventional method.

The cyclization reaction (c) with hydrazine, which is preferably used inthe form of the hydrate, is advantageously carried out in a solvent, inparticular a lower alcohol, such as methanol, ethanol or propanol, acyclic aliphatic ether, such as tetrahydrofuran or dioxane, or adialkylamide, in particular dimethylformamide or N-methylpyrrolidone, atfrom 20° to 150° C., preferably from 50° to 100° C. In this reaction, asa rule, 1 mole of hydrazine or hydrazine hydrate is used per mole of XI.

Reaction (d) is advantageously carried out in a solvent, such as a loweralkanol, eg. methanol, ethanol is isopropanol, or a dialkylamide, eg.dimethylformamide or N-methylpyrrolidone, in the presence of a base, eg.NaOH, KOH or K₂ CO₃, or of a tertiary amine, at from 20° to 150° C.,preferably from 50° to 100° C. Advantageously, from 1 to 1.5 moles offormaldehyde are used per mole of I (where A, B and R² are each H). Thereaction can be carried out under atmospheric or superatmosphericpressure.

The compounds of the formula XI which are used as starting materials canbe prepared by acylating an aminoacid of the formula XII ##STR11## whereA, B, R¹ and R² have the meanings given for formula I, with a compoundof the formula X under the conditions stated for the acylation of acompound of the formula IX with a compound of the formula X, and, wherethe resulting compound is the hydrochloride or the hydrobromide of acompound of the formula XI, converting this product to the free aminoacid.

The compounds of the formula XII are known, or can be prepared by aconventional method.

The compounds listed in the Tables below can be prepared by theprocesses described.

                  TABLE 1    ______________________________________    Compounds I in which A and B are each H, R.sup.3 is CH.sub.2CH.sub.2    and the radical R.sup.4R.sup.3CONHis on the para-position    R.sup.4                 R.sup.1  R.sup.2    ______________________________________     ##STR12##              H        H     ##STR13##              CH.sub.3 H     ##STR14##              CH.sub.2     ##STR15##              H        H     ##STR16##              CH.sub.2     ##STR17##              CH.sub.3 H     ##STR18##              CH.sub.3 H     ##STR19##              CH.sub.2     ##STR20##              H        H     ##STR21##              CH.sub.3 H     ##STR22##              CH.sub.3 H     ##STR23##              CH.sub.2     ##STR24##              CH.sub.2 CH.sub.2     ##STR25##              CH.sub.3 H     ##STR26##              CH.sub.3 H     ##STR27##              CH.sub.3 H     ##STR28##              CH.sub.3 H     ##STR29##              H        H     ##STR30##              CH.sub.2     ##STR31##              CH.sub.3 H     ##STR32##              CH.sub.3 H     ##STR33##              CH.sub.3 H     ##STR34##              H        H     ##STR35##              CH.sub.2     ##STR36##              H        H     ##STR37##              CH.sub.3 H     ##STR38##              CH.sub.3 H     ##STR39##              H        H     ##STR40##              CH.sub.2     ##STR41##              CH.sub.2     ##STR42##           CH.sub.2CH.sub.2CH.sub.2     ##STR43##              CH.sub.2     ##STR44##              CH.sub.2 CH.sub.2     ##STR45##              CH.sub.3 H     ##STR46##              H        H     ##STR47##              CH.sub.3 H     ##STR48##              CH.sub.3 H     ##STR49##              CH.sub.3 H     ##STR50##              CH.sub.3 H     ##STR51##              H        H     ##STR52##              CH.sub.2     ##STR53##              CH.sub.3 H     ##STR54##              CH.sub.3 H     ##STR55##              CH.sub.2CH.sub.2     ##STR56##              CH.sub.3 H     ##STR57##              CH.sub.3 H     ##STR58##              CH.sub.3 H     ##STR59##              CH.sub.3 H     ##STR60##              CH.sub.3 H     ##STR61##              CH.sub.3 H     ##STR62##              H        H     ##STR63##              CH.sub.2     ##STR64##              CH.sub.3 H     ##STR65##              CH.sub.3 H     ##STR66##              CH.sub.3 H     ##STR67##              CH.sub.3 H     ##STR68##              CH.sub.3 H     ##STR69##              CH.sub.2     ##STR70##              H        H     ##STR71##              CH.sub.2     ##STR72##              H        H     ##STR73##              CH.sub.2     ##STR74##              CH.sub.2     ##STR75##              CH.sub.3 H     ##STR76##              CH.sub.3 H     ##STR77##              CH.sub.3 H     ##STR78##              CH.sub.3 H     ##STR79##              CH.sub.3 H     ##STR80##              CH.sub.3 H     ##STR81##              CH.sub.3 H     ##STR82##              CH.sub.3 H     ##STR83##              CH.sub.3 H     ##STR84##              CH.sub.3 H     ##STR85##              CH.sub. 3                                     H     ##STR86##              CH.sub.2     ##STR87##              CH.sub.3 H     ##STR88##              CH.sub.3 H     ##STR89##              CH.sub.3 H     ##STR90##              CH.sub.3 H     ##STR91##              CH.sub.3 H     ##STR92##              CH.sub.3 H     ##STR93##              H        H     ##STR94##              CH.sub.2     ##STR95##              CH.sub.3 H     ##STR96##              CH.sub.2     ##STR97##              H        H     ##STR98##              CH.sub.3 H     ##STR99##              CH.sub.3 H     ##STR100##             CH.sub.2     ##STR101##             H        H     ##STR102##             CH.sub.3 H     ##STR103##             H        H     ##STR104##             CH.sub.3 H     ##STR105##             H        H     ##STR106##             CH.sub.2     ##STR107##             H        H     ##STR108##             CH.sub.3 H     ##STR109##             CH.sub.3 H     ##STR110##             CH.sub.3 H     ##STR111##             CH.sub.2     ##STR112##          CH .sub.2CH .sub.2CH.sub.2 CH .sub.2     ##STR113##             CH.sub.3 H     ##STR114##             H        H     ##STR115##             CH.sub.3 H     ##STR116##             CH.sub.3 H     ##STR117##             CH.sub.3 H     ##STR118##             CH.sub.3 H     ##STR119##             CH.sub.3 H     ##STR120##             CH.sub.3 H     ##STR121##             CH.sub.3 H     ##STR122##             CH.sub.3 H     ##STR123##             CH.sub.3 H     ##STR124##             CH.sub.3 H     ##STR125##             CH.sub.2     ##STR126##             CH.sub.3 H     ##STR127##             CH.sub.3 H     ##STR128##             CH.sub.3 H     ##STR129##             CH.sub.3 H     ##STR130##             CH.sub.3 H     ##STR131##             CH.sub.3 H     ##STR132##             CH.sub.3 H     ##STR133##             CH.sub.3 H     ##STR134##             CH.sub.3 H     ##STR135##             CH.sub.3 H     ##STR136##             CH.sub.3 H     ##STR137##             CH.sub.3 H     ##STR138##             CH.sub.3 H     ##STR139##             CH.sub.3 H     ##STR140##             CH.sub.3 H     ##STR141##             CH.sub.3 H     ##STR142##             CH.sub.3 H     ##STR143##             CH.sub.3 H     ##STR144##             CH.sub.3 H     ##STR145##             CH.sub.3 H     ##STR146##             CH.sub.3 H     ##STR147##             CH.sub.3 H     ##STR148##             CH.sub.3 H     ##STR149##             CH.sub.3 H     ##STR150##             CH.sub.3 H     ##STR151##             CH.sub.3 H     ##STR152##             CH.sub.3 H     ##STR153##             CH.sub.3 H    (C.sub.6 H.sub.5).sub.2 CHNH                            CH.sub.3 H    (C.sub.6 H.sub.5).sub.2 CHCH.sub.2NH                            CH.sub.3 H    (C.sub.6 H.sub.5).sub.2 CHCH.sub.2CH.sub.2NH                            CH.sub.3 H     ##STR154##             CH.sub.3 H     ##STR155##             CH.sub.3 H     ##STR156##             CH.sub.3 H     ##STR157##             CH.sub.3 H     ##STR158##             CH.sub.3 H     ##STR159##             CH.sub.3 H     ##STR160##             CH.sub.3 H     ##STR161##             CH.sub.3 H     ##STR162##             CH.sub.3 H     ##STR163##             CH.sub.3 H     ##STR164##             CH.sub.3 H     ##STR165##             CH.sub.3 H     ##STR166##             CH.sub.3 H     ##STR167##             CH.sub.3 H     ##STR168##             CH.sub.3 H     ##STR169##             CH.sub.3 H     ##STR170##             CH.sub.3 H     ##STR171##             CH.sub.3 H     ##STR172##             CH.sub.3 H     ##STR173##             CH.sub.3 H     ##STR174##             CH.sub.3 H     ##STR175##             CH.sub.3 H     ##STR176##             CH.sub.3 H     ##STR177##             CH.sub.3 H     ##STR178##             CH.sub.3 H     ##STR179##             CH.sub.3 H     ##STR180##             H        H     ##STR181##             CH.sub.3 H     ##STR182##             H        H    C.sub.6 H.sub.5 CH.sub.2 CH.sub.2NH                            CH.sub.3 H     ##STR183##             CH.sub.3 H    cyclo-C.sub.3 H.sub.5NH CH.sub.3 H    cyclo-C.sub.6 H.sub.11NH                            CH.sub.2     ##STR184##             CH.sub.2     ##STR185##             CH.sub.2 CH.sub.2     ##STR186##             H        H     ##STR187##             CH.sub.3 H     ##STR188##             CH.sub.3 H    (n-C.sub.8 H.sub.17).sub.2 N                            CH.sub.3 H    (n-C.sub.4 H.sub.9).sub.2 N                            CH.sub.2     ##STR189##             CH.sub.2     ##STR190##             CH.sub.3 H     ##STR191##             CH.sub.3 H     ##STR192##             H        H     ##STR193##             CH.sub.3 H     ##STR194##             CH.sub.2     ##STR195##             CH.sub.3 H     ##STR196##             CH.sub.2     ##STR197##             CH.sub.3 H     ##STR198##             CH.sub.2     ##STR199##             CH.sub.3 H     ##STR200##             CH.sub.3 H     ##STR201##             CH.sub.3 H     ##STR202##             H        H     ##STR203##             CH.sub.3 H     ##STR204##             CH.sub.3 H     ##STR205##             CH.sub.3 H     ##STR206##             H        H     ##STR207##             CH.sub.2     ##STR208##             CH.sub.2     ##STR209##             CH.sub.3 H     ##STR210##             CH.sub.3 H     ##STR211##             CH.sub.2     ##STR212##             CH.sub.3 H     ##STR213##             H        H     ##STR214##             CH.sub.3 H     ##STR215##             CH.sub.3 H     ##STR216##             CH.sub.3 H     ##STR217##             CH.sub.3 H     ##STR218##             H        H     ##STR219##             CH.sub.3 H     ##STR220##             CH.sub.3 H     ##STR221##             CH.sub.3 H     ##STR222##             CH.sub.3 H     ##STR223##             CH.sub.2     ##STR224##             CH.sub.2     ##STR225##             CH.sub.3 H     ##STR226##             CH.sub.3 H     ##STR227##             CH.sub.3 H     ##STR228##             CH.sub.3 H     ##STR229##             CH.sub.3 H     ##STR230##             CH.sub.3 H     ##STR231##             CH.sub.3 H     ##STR232##             CH.sub.3 H     ##STR233##             CH.sub.3 H     ##STR234##             CH.sub.3 H     ##STR235##             CH.sub.3 H     ##STR236##             CH.sub.3 H     ##STR237##             CH.sub.3 H     ##STR238##             CH.sub.3 H     ##STR239##             CH.sub. 3                                     H     ##STR240##             CH.sub.3 H     ##STR241##             CH.sub.3 H     ##STR242##             CH.sub.3 H     ##STR243##             CH.sub.3 H     ##STR244##             H        H     ##STR245##             CH.sub.3 H     ##STR246##             CH.sub.3 H     ##STR247##             CH.sub.3 H     ##STR248##             CH.sub.3 H     ##STR249##             CH.sub.3 H     ##STR250##             CH.sub.3 H     ##STR251##             CH.sub.3 H     ##STR252##             CH.sub.3 H     ##STR253##             CH.sub.3 H     ##STR254##             CH.sub.3 H     ##STR255##             CH.sub.3 H     ##STR256##             CH.sub.3 H     ##STR257##             CH.sub.3 H     ##STR258##             CH.sub.3 H     ##STR259##             CH.sub.3 H    ______________________________________

                  TABLE 2    ______________________________________    Compounds I in which A and B are each H,     ##STR260##    is in the para-position    R.sup.4                 R.sup.1  R.sup.2    ______________________________________     ##STR261##             CH.sub.3 H     ##STR262##             H        H     ##STR263##             CH.sub.2     ##STR264##             CH.sub.3 H     ##STR265##             H        H     ##STR266##             CH.sub.2     ##STR267##             CH.sub.3 H     ##STR268##             CH.sub.3 H     ##STR269##             CH.sub.3 H     ##STR270##             H        H    ______________________________________

                  TABLE 3    ______________________________________    Compounds I in which A and B are each H,     ##STR271##    is in the para-position    R.sup.4               R.sup.1    R.sup.2    ______________________________________     ##STR272##           CH.sub.3   H     ##STR273##           CH.sub.2     ##STR274##           CH.sub.2CH.sub.2     ##STR275##           CH.sub.3   H     ##STR276##           CH.sub.3   H     ##STR277##           CH.sub.3   H     ##STR278##           CH.sub.3   H     ##STR279##           CH.sub.2     ##STR280##           CH.sub.3   H     ##STR281##           CH.sub.3   H     ##STR282##           CH.sub.3   H     ##STR283##           CH.sub.2     ##STR284##           CH.sub. 3  H     ##STR285##           CH.sub.2     ##STR286##           CH.sub.3   H     ##STR287##           CH.sub.3   H     ##STR288##           CH.sub.2     ##STR289##           CH.sub.3   H     ##STR290##           CH.sub.3   H     ##STR291##           CH.sub.3   H     ##STR292##           CH.sub.2     ##STR293##           CH.sub.3   H     ##STR294##           CH.sub.3   H     ##STR295##           CH.sub.3   H     ##STR296##           CH.sub.3   H     ##STR297##           CH.sub.3   H    cyclo-C.sub.6 H.sub.11NH                          CH.sub.3   H     ##STR298##           CH.sub.3   H     ##STR299##           CH.sub.2     ##STR300##           CH.sub.3   H     ##STR301##           CH.sub.3   H    ______________________________________

                  TABLE 4    ______________________________________    Compounds I in which A and B are each H, R.sup.3 is CH.sub.2,    and the radical R.sup.4R.sup.3CONHis in the para-position    R.sup.4                 R.sup.1                                   R.sup.2    ______________________________________     ##STR302##             CH.sub.3                                   H     ##STR303##             CH.sub.2     ##STR304##             CH.sub.3                                   H     ##STR305##             CH.sub.3                                   H     ##STR306##             CH.sub.3                                   H     ##STR307##             CH.sub. 2     ##STR308##             CH.sub.3                                   H     ##STR309##             CH.sub.2     ##STR310##             CH.sub.3                                   H     ##STR311##             CH.sub.3                                   H     ##STR312##             CH.sub.3                                   H     ##STR313##             CH.sub.3                                   H     ##STR314##             CH.sub.3                                   H     ##STR315##             CH.sub.3                                   H    ______________________________________

                  TABLE 5    ______________________________________    Compounds I in which A and B are each H, R.sup.3 is    CH.sub.2 CH.sub.2 CH.sub.2, and the radical R.sup.4R.sup.3CONH    is in the para-position    R.sup.4               R.sup.1  R.sup.2    ______________________________________     ##STR316##           CH.sub.2 CH.sub.2     ##STR317##           CH.sub.2 CH.sub.2 CH.sub.2     ##STR318##           CH.sub.3 H     ##STR319##           CH.sub.3 H     ##STR320##           CH.sub.2     ##STR321##           CH.sub.3 H     ##STR322##           H        H     ##STR323##           CH.sub.3 H     ##STR324##           H        H     ##STR325##           CH.sub.3 H     ##STR326##           CH.sub.3 H     ##STR327##           CH.sub.2     ##STR328##           CH.sub.3 H     ##STR329##           CH.sub.3 H     ##STR330##           CH.sub.3 H    C.sub.6 H.sub.5 CH.sub.2 NH                          CH.sub.3 H     ##STR331##           CH.sub.3 H     ##STR332##           CH.sub.3 H     ##STR333##           CH.sub.3 H     ##STR334##           CH.sub.3 H    ______________________________________

                  TABLE 6    ______________________________________    Compounds I in which A and B are each H, R.sup.3 is (CH.sub.2).sub.4,    and the radical R.sup.4R.sup.3CONH is in the para-position    R.sup.4               R.sup.1                                 R.sup.2    ______________________________________     ##STR335##           CH.sub.3                                 H     ##STR336##           CH.sub.3                                 H     ##STR337##           CH.sub.3                                 H    ______________________________________

                  TABLE 7    ______________________________________     ##STR338##    and the radical R.sup.4R.sup.3CONH is in the para-position    R.sup.4                 R.sup.1                                   R.sup.2    ______________________________________     ##STR339##             H      H     ##STR340##             CH.sub.3                                   H     ##STR341##             CH.sub.2     ##STR342##             CH.sub.3                                   H     ##STR343##             H      H     ##STR344##             H      H     ##STR345##             CH.sub.3                                   H     ##STR346##             CH.sub.3                                   H    ______________________________________

                  TABLE 8    ______________________________________     ##STR347##    and the radical R.sup.4R.sup.3CONH is in the para-position    R.sup.4                 R.sup.1                                   R.sup.2    ______________________________________     ##STR348##             H      H     ##STR349##             CH.sub.3                                   H     ##STR350##             CH.sub.2     ##STR351##             H      H     ##STR352##             CH.sub.3                                   H     ##STR353##             CH.sub.2     ##STR354##             CH.sub.3                                   H     ##STR355##             CH.sub.3                                   H    ______________________________________

                  TABLE 9    ______________________________________    Compounds I in which A and B are each H,     ##STR356##    in the para-position    R.sup.4                 R.sup.1                                   R.sup.2    ______________________________________     ##STR357##             H      H     ##STR358##             CH.sub.3                                   H     ##STR359##             CH.sub.2     ##STR360##             H      H     ##STR361##             CH.sub.3                                   H     ##STR362##             CH.sub.2     ##STR363##             CH.sub.3                                   H     ##STR364##             CH.sub.3                                   H    ______________________________________

                  TABLE 10    ______________________________________     ##STR365##    and the radical R.sup.4R.sup.3CONH is in the para-position    R.sup.4                 R.sup.1                                   R.sup.2    ______________________________________     ##STR366##             H      H     ##STR367##             CH.sub.3                                   H     ##STR368##             H      H     ##STR369##             CH.sub.3                                   H     ##STR370##             CH.sub.2     ##STR371##             CH.sub.3                                   H     ##STR372##             CH.sub.3                                   H    ______________________________________

                  TABLE 11    ______________________________________    Compounds I in which A and B together constitute a bond,    R.sup.3 is CH.sub.2 CH.sub.2, and the radical R.sup.4R.sup.3CONH is in    the    para-position    R.sup.4                 R.sup.1 R.sup.2    ______________________________________     ##STR373##             H       H     ##STR374##             H       CH.sub.3     ##STR375##             H       H     ##STR376##             H       CH.sub.3     ##STR377##             H       H     ##STR378##             H       H     ##STR379##             H       CH.sub.3     ##STR380##             H       H     ##STR381##             H       H     ##STR382##             H       CH.sub.3     ##STR383##             H       H     ##STR384##             H       H     ##STR385##             H       H     ##STR386##             H       H     ##STR387##             H       CH.sub.3     ##STR388##             H       H     ##STR389##             H       H     ##STR390##             H       H     ##STR391##             H       H     ##STR392##             H       CH.sub.3     ##STR393##             H       H    ______________________________________

                  TABLE 12    ______________________________________    Compounds I in which A and B together constitute a bond,     ##STR394##    para-position    R.sup.4              R.sup.1  R.sup.2    ______________________________________     ##STR395##          H        H     ##STR396##          H        H     ##STR397##          H        CH.sub.3     ##STR398##          H        CH.sub.3     ##STR399##          H        H     ##STR400##          H        H     ##STR401##          H        H     ##STR402##          H        H    ______________________________________

                  TABLE 13    ______________________________________    Compounds I in which A and B together constitute a bond,    R.sup.3 is (CH.sub.2).sub.3, and the radical R.sup.4R.sup.3CONH is in    the    para-position    R.sup.4                 R.sup.1 R.sup.2    ______________________________________     ##STR403##             H       H     ##STR404##             H       H     ##STR405##             H       H     ##STR406##             H       CH.sub.3     ##STR407##             H       H     ##STR408##             H       H     ##STR409##             H       H     ##STR410##             H       CH.sub.3    ______________________________________

                  TABLE 14    ______________________________________    Compounds I in which A and B are each H, R.sup.3 is CH.sub.2 CH.sub.2,    and the radical R.sup.4R.sup.3CONH is in the meta-position    R.sup.4                 R.sup.1  R.sup.2    ______________________________________     ##STR411##             CH.sub.2     ##STR412##             CH.sub.2 CH.sub.2     ##STR413##             H        H     ##STR414##             CH.sub.3 H     ##STR415##             CH.sub.3 H     ##STR416##             CH.sub.3 H     ##STR417##             CH.sub.3 H     ##STR418##             CH.sub.3 H     ##STR419##             CH.sub.3 H     ##STR420##             CH.sub.3 H     ##STR421##             CH.sub.3 H     ##STR422##             CH.sub.3 H     ##STR423##             CH.sub.3 H     ##STR424##             CH.sub.3 H     ##STR425##             CH.sub.3 H    ______________________________________

                  TABLE 15    ______________________________________     ##STR426##    and the radical R.sup.4R.sup.3CONH is in the meta-position    R.sup.4               R.sup.1   R.sup.2    ______________________________________     ##STR427##           CH.sub.3  H     ##STR428##           CH.sub.2     ##STR429##           CH.sub.3  H     ##STR430##           CH.sub.2     ##STR431##           H         H    ______________________________________

Compounds I in which A, B and R² are each hydrogen and R¹ is nothydrogen (4,5-dihydro-3(2H)-pyridazinones) have an asymmetric carbonatom in the 5-position and are therefore normally obtained in the formof their racemates. The present invention also relates to theenantiomers; advantageously, resolution is effected at the stage ofcompound IX (if in this compound A, B and R² are each hydrogen) in aconventional manner, for example by formation of diastereomeric saltswith an optically active carboxylic acid, eg. dibenzoyltartaric acid orcamphor-10-sulfonic acid, and the enantiomers are obtained by separatereaction of the resulting optically active precursors.

Compounds of the formula I in which R³ is a substituted alkylene groupcan contain an asymmetric carbon atom in this alkylene chain. Thepresent invention also relates to the enantiomers, which can beseparated in a conventional manner, for example by formation ofdiastereomeric salts with an optically active carboxylic acid orsulfonic acid, or can be obtained by using appropriate optically activeprecursors, such as the compounds of the formulae VII, X and XI.

Furthermore, the compounds I can possess asymmetric carbon atoms in theamine moiety R⁴. They are preferably prepared starting from theoptically active amines VIII, by reaction with a compound VII or via theintermediates X or XI.

Compounds I in which R¹ and R² together form a methylene, ethylene,propylene or butylene group (3,4-diazabicyclo[4.1.0]heptenones,3,4-diazabicyclo[4.2.0]octenones, 3,4-diazabicyclo[4.3.0]nonenones and3,4-diazabicyclo[4.4.0]decanones) also form racemates, owing to thepresence of the asymmetric carbon atoms 1 and 6 of the3,4-diazabicyclo[4.n.0]alk-2-en-5-one ring. The present invention alsorelates to the enantiomers obtainable from these racemates.

In particular, the novel compounds of the formula I and their salts witha pharmaceutically tolerated acid inhibit thrombocyte aggregation andgastric secretion and have hypotensive and positively inotropicproperties.

The following methods were used to examine the pharmacodynamicproperties of the products according to the invention:

1. Inhibition of the collagen-induced aggregation of human thrombocytesin vitro.

Thrombocyte-rich plasma is obtained by centrifuging venous citrate blood(300 g, 10 minutes duration at 4° C.). Photometric measurement of thethrombocyte aggregation is carried out with the addition of MgCl₂ (finalconcentration 10 millimoles/liter) and of collagen Stago (finalconcentration 0.02 mg/ml) in a Born Mk 3 aggregometer. The maximumextinction change/sec. is used as a measure of the aggregation.

The aggregation-inhibiting activity of the substances is tested after anincubation time of 10 minutes.

The EC 50% is taken to be the concentration causing 50% inhibition ofaggregation.

2. Hypotensive action on anesthetized rats.

To test the hypotensive effect, the substances are administeredintraperitoneally or intravenously to groups of 3-5 male Sprague-Dawleyrats weighing 240-280 g, under urethane anesthesia (1.78 mg/kg,administered intraperitoneally).

The measurement of the blood pressure in the carotid artery is carriedout by means of Statham transducers. The ED 20% is determined as thedose which lowers the mean carotid blood pressure by 20%.

3. Inhibition of gastric secretion

Inhibition of the secretion of gastric acid results in an increase inthe pH of the gastric mucous membrane. It is investigated on groups of 4female Sprague-Dawley rats weighing 160-180 g. The animals fast for 48hours (water ad libitum), and are pretreated with various doses(administered orally). After 1 hour, they are anesthetized with Nahexabarbital (46.4 mg/kg, administered intravenously), after which a pHelectrode (Philips type CJP special electrode) is introduced into thestomach and the pH on the surfaace of the gastric mucous membrane ismeasured (pH for untreated animals: 1.40±0.002; N=200). The ED 0.75, ie.the dose which increases the pH by an average of 0.75 compared withuntreated control animals, is determined from the linear regressionbetween the logarithms of the doses administered and of the increase inpH.

In these tests, the novel substances are effective in very low doses.

Accordingly, the present invention also relates to therapeutic agents orformulations which, in addition to conventional pharmaceuticalexcipients and diluents, contain a compound of the formula I or its saltas an active compound, and to the use of these compounds for therapeuticpurposes.

The therapeutic agents or formulations can be prepared in a conventionalmanner by compounding an appropriate dose with the conventionalexcipients or diluents and the conventionally used pharmaceuticalauxiliaries, in accordance with the desired route of administration.Suitable doses for man are from 0.1 to 100 mg, oral administration beingpreferred.

Examples of suitable forms for oral administration are tablets, filmtablets, coated tablets, capsules, pills, powders, solutions,suspensions or depot forms.

For practical use, the compounds employed according to the invention areformulated with the excipients conventionally used in pharmaceuticalproduction. For example, appropriate tablets can be obtained by mixingthe active compound with conventional auxiliaries, for example inertdiluents, such as dextrose, sugar, sorbitol, polyvinylpyrrolidone,mannitol, calcium carbonate, calcium phosphate or lactose,disintegrating agents, eg. corn starch, alginic acid orpolyvinylpyrrolidone, binders, eg. starch or gelatine, lubricants, eg.magnesium stearate or talc, and/or agents for achieving a depot effect,eg. carboxypolymethylene, carboxymethylcellulose, cellulose acetatephthalate or polyvinyl acetate. The tablets can also consist of aplurality of layers (cf. H. Sucker et al, Pharmazeutische Technologie,Thieme Verlag, Stuttgart 1978).

Accordingly, coated tablets may be prepared by coating cores, preparedsimilarly to the tablets, with agents conventionally used in tabletcoatings, eg. polyvinylpyrrolidone, shellac, gum arabic, talc, titaniumdioxide or sugar. The tablet shell can also consist of several layers,in which the auxiliaries mentioned above in connection with the tabletsmay be used.

The Examples which follow illustrate the preparation of the novel6-(acylaminoaryl)-3(2H)-pyridazinones.

EXAMPLE 1

5.8 g (20 millimoles) of6-[p-(3-chloropropionylamino]-4,5-dihydro-3(2H)-pyridazinone werestirred with 3.5 g (25 millimoles) of potassium carbonate and 2.17 g (25millimoles) of morpholine in 50 ml of dimethylformamide for 8 hours at80° C. 500 g of ice/water were added, after which the crystals werefiltered off under suction and recrystallized fromdimethylformamide/water. The product was dried under greatly reducedpressure at 50° C. to give 5.4 g (82%) of6-[p-3-(1-morpholino)-propionylaminophenyl]-B4,5-dihydro-3(2H)-pyridazinone as colorless crystals of melting point183°-185° C.

The compounds of Examples 2 to 104 were prepared similarly to Example 1.If the compounds are obtained in the form of oils, they can be purifiedby extraction with methylene chloride and/or column chromatography oversilica gel or alumina using a methylene chloride/methanol mixture as themobile phase.

    __________________________________________________________________________     ##STR432##    Example    No.  R.sup.4R.sup.3 [X H.sub.2 O]       R.sup.1                                                   R.sup.2                                                         Mp.                                                              A and    __________________________________________________________________________                                                              Be.C.]    2    (H.sub.3 C).sub.2 NCH.sub.2 CH.sub.2                                      [1/2 H.sub.2 O]                                            CH.sub.3                                                   H     74-75                                                              HH    3    (H.sub.3 C).sub.2 NCH.sub.2 CH.sub.2                                            H      H     168-170                                                              HH          ##STR433##                  [1 H.sub.2 O]                                            CH.sub.3                                                   H     143-145                                                              HH    5          ##STR434##                  [1,5 H.sub.2 O]                                            H      H     168-170                                                              HH    6          ##STR435##                        CH.sub.3                                                   H     87-89                                                              HH    7          ##STR436##                  [1 H.sub.2 O]                                            H      H     165-166                                                              HH    8          ##STR437##                  [1 H.sub.2 O]                                            CH.sub.3                                                   H     119-121                                                              HH    9          ##STR438##                        H      H     191-192                                                              HH    10          ##STR439##                  [1/2 H.sub.2 O]                                            CH.sub.3                                                   H     180-183                                                              HH    11          ##STR440##                  [1/4 H.sub.2 O]                                            H      H     160-162                                                              HH    12          ##STR441##                        CH.sub.3                                                   H     228-230                                                              HH    13          ##STR442##                  [1/4 H.sub.2 O]                                            H      H     238-240                                                              HH    14          ##STR443##                  [1 H.sub.2 O]                                            CH.sub.2     244-247                                                              HH    15          ##STR444##                        CH.sub.2CH.sub.2                                                         240-241                                                              HH    16          ##STR445##                        CH.sub.3                                                   H          HH    17          ##STR446##                        CH .sub. 2CH .sub.2CH .sub.2CH                                            .sub.2       191-192                                                              HH    18          ##STR447##                        CH.sub.3                                                   H     148-150                                                              HH    19          ##STR448##                  [1 H.sub.2 O]                                            H      H     150-152                                                              HH    20          ##STR449##                  [1/4 H.sub.2 O]                                            CH.sub.2     154-155                                                              HH    21          ##STR450##                  [1.25 H.sub.2 O]                                            CH.sub.2CH.sub.2                                                         115-117                                                              HH    22          ##STR451##                        CH.sub. 3                                                   H     216-217                                                              HH    23          ##STR452##                  [H.sub.2 O]                                            CH.sub.3                                                   H     208-210                                                              HH    24          ##STR453##                        CH.sub.3                                                   H     239-240                                                              HH    25          ##STR454##                  [H.sub.2 O]                                            CH.sub.3                                                   H     113-115                                                              HH    26          ##STR455##                  [H.sub.2 O]                                            H      H     197-199                                                              HH    27          ##STR456##                  [1 H.sub.2 O]                                            CH.sub.3                                                   H     168-169                                                              HH    28          ##STR457##                        CH.sub.3                                                   H     245-247                                                              HH    29          ##STR458##                        H      H     261-263                                                              HH    30          ##STR459##                  [1 H.sub.2 O]                                            CH.sub.3                                                   H     204-206                                                              HH    31          ##STR460##                        H      H     235-236                                                              HH    32          ##STR461##                  [1 H.sub.2 O]                                            CH.sub.3                                                   H     200-201                                                              HH    33          ##STR462##                        CH.sub.3                                                   H     210-212                                                              HH    34          ##STR463##                  [1/2 H.sub.2 O]                                            CH.sub.3                                                   H     187-188                                                              HH    35          ##STR464##                        H      H     216-218                                                              HH    36          ##STR465##                  [1 H.sub.2 O]                                            CH.sub.3                                                   H     190-192                                                              HH    37          ##STR466##                        H      H     192-194                                                              HH    38          ##STR467##                        CH.sub.2                                                   H     223-225                                                              HH    39          ##STR468##                        CH.sub.3                                                   H     145-147                                                              HH    40          ##STR469##                  [1/2 H.sub.2 O]                                            H      H     235-236                                                              HH    41          ##STR470##                        H      H     207-209                                                              HH    42          ##STR471##                  [1/2 H.sub.2 O]                                            CH.sub.3                                                   H     86-89                                                              HH    43          ##STR472##                  [1.5 H.sub.2 O]                                            CH.sub.3                                                   H     261-263                                                              HH    44          ##STR473##                        H      H     255-257                                                              HH    45          ##STR474##                  [1 H.sub.2 O]                                            CH.sub.3                                                   H     228-230                                                              HH    46          ##STR475##                        H      H     219-221                                                              HH    47          ##STR476##                  [1/4 H.sub.2 O]                                            CH.sub.3                                                   H     178-179                                                              HH    48          ##STR477##                  [1 H.sub.2 O]                                            H      H     171-173                                                              HH    49          ##STR478##                  [1 H.sub.2 O]                                            H      H     134-136                                                              HH    50          ##STR479##                        H      H     200-202                                                              HH    51          ##STR480##                  [1.5 H.sub.2 O]                                            CH.sub.3                                                   H     193-195                                                              HH    52          ##STR481##                  [1/4 H.sub.2 O]                                            H      H     252-254                                                              HH    53          ##STR482##                  [1 H.sub.2 O]                                            H      H     224-225                                                              HH    54          ##STR483##                  [1 H.sub.2 O]                                            CH.sub.3                                                   H     198-200                                                              HH    55          ##STR484##                  [1/2 H.sub.2 O]                                            H      H     248-251                                                              HH    56          ##STR485##                        CH.sub.3                                                   H     170-171                                                              HH    57          ##STR486##                  [1 H.sub.2 O]                                            CH.sub.2     199-200                                                              HH    58          ##STR487##                        CH.sub.2     184-185                                                              HH    59          ##STR488##                        CH.sub.3                                                   H     200-202                                                              HH    60          ##STR489##                  [1 H.sub.2 O]                                            CH.sub.2     194-195                                                              HH    61          ##STR490##                  [1 H.sub.2 O]                                            CH.sub.3                                                   H     112-113                                                              HH    62          ##STR491##                  [1/2 H.sub.2 O]                                            CH.sub.3                                                   H     295-297                                                              HH    63          ##STR492##                  [1/2 H.sub.2 O]                                            H      H     129-130                                                              HH    64          ##STR493##                  [1/2 H.sub.2 O]                                            CH.sub.3                                                   H     115-117                                                              HH    65          ##STR494##                  [1/2 H.sub.2 O]                                            H      H     190-192                                                              HH    66          ##STR495##                        CH.sub.3                                                   H     118-124                                                              HH    67          ##STR496##                        CH.sub.2CH.sub.2  HH    68          ##STR497##                        CH.sub.3                                                   H     92-96                                                              HH    69          ##STR498##                  [3/4 H.sub.2 O]                                            H      H     129-130                                                              HH    70          ##STR499##                        H      H     263-265                                                              HH    71          ##STR500##                        H      H     207-209                                                              HH    72          ##STR501##                        H      H     183-184                                                              HH    73          ##STR502##                        CH.sub.3                                                   H     63-65                                                              HH    74          ##STR503##                        CH.sub.2     265-267                                                              HH    75          ##STR504##                        H      H     121-123                                                              HH    76          ##STR505##                        CH.sub.3                                                   H          HH    77          ##STR506##                        CH.sub.3                                                   H     60-66                                                              HH    78          ##STR507##                        CH.sub.3                                                   H          HH    79          ##STR508##                        CH.sub.3                                                   H     232-234                                                              HH    80          ##STR509##                        CH.sub.3                                                   H     201-202                                                              HH    81          ##STR510##                        CH.sub.3                                                   H          HH    82          ##STR511##                        CH.sub.3                                                   H     185-187                                                              HH    83          ##STR512##                        CH.sub.3                                                   H     oil  HH    84          ##STR513##                        CH.sub.3                                                   H     132-135                                                              HH    85          ##STR514##                        CH.sub.3                                                   H     115-120                                                              HH    86          ##STR515##                        CH.sub.3                                                   H     oil  HH    87          ##STR516##                        CH.sub.3                                                   H     oil  HH    88          ##STR517##                        CH.sub.3                                                   H     200-202                                                              HH    89          ##STR518##                        CH.sub.3                                                   H     187-189                                                              HH    90          ##STR519##                        CH.sub.3                                                   H     85-87                                                              HH    91          ##STR520##                        CH.sub.3                                                   H     183-185                                                              HH    92          ##STR521##                        CH.sub.3                                                   H     oil  HH    93   n-C.sub.12 H.sub. 25NHCH.sub.2CH.sub.2                                            CH.sub.3                                                   H     123-124                                                              HH    94          ##STR522##                        CH.sub.3                                                   H     58-60                                                              HH    95          ##STR523##                        CH.sub.3                                                   H     85-87                                                              HH    96          ##STR524##                        CH.sub.3                                                   H     149-150                                                              HH    97   1-Adamantyl-NHCH.sub.2CH.sub.2     CH.sub.3                                                   H     122-126                                                              HH    98          ##STR525##                        CH.sub.3                                                   H     75-78                                                              HH    99          ##STR526##                        CH.sub.3                                                   H     139-142                                                              HH    100          ##STR527##                        H      H     175-177                                                              HH    101          ##STR528##                        CH.sub.3                                                   H          HH    102          ##STR529##                        CH.sub.3                                                   H          HH    103          ##STR530##                        CH.sub.3                                                   H          HH    104          ##STR531##                        CH.sub.3                                                   H     190-192                                                              HH    __________________________________________________________________________

The compounds of Examples 105 to 107 were obtained similarly to Example1, by conversion of6-[m-(3-chloropropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

    ______________________________________     ##STR532##    Example    No.    R.sup.4R.sup.3[X H.sub.2 O]                               R.sup.1                                      R.sup.2                                          Mp. [°C.]    ______________________________________    105            ##STR533##         CH.sub.3                                      H   189-190    106            ##STR534##         H      H   182-183    107            ##STR535##         H      H   154-156    ______________________________________

The compounds of Examples 108 to 117 were obtained from6-[p-(3-chloropropionylamino)-phenyl]-3(2H)-pyridazinone,6-[p-(3-chloropropionylamino)-phenyl]-5-methyl-3(2H)-pyridazinone or6-[p-(3-chloropropionylamino)-phenyl]-4-methyl-3(2H)-pyridazinone by amethod similar to that described in Example 1.

    ______________________________________     ##STR536##    Ex-    am-    ple                                     Mp.    No.  R.sup.4R.sup.3[X H.sub.2 O]                                R.sup.1                                       R.sup.2                                            [°C.]    ______________________________________    108          ##STR537##            H      H    235- 237    109          ##STR538##            H      H    110          ##STR539##            H      H    111          ##STR540##            H      H    112          ##STR541##            H      H    113          ##STR542##            H      H    114          ##STR543##            CH.sub.3                                       H    115          ##STR544##            CH.sub.3                                       H    116          ##STR545##            H      CH.sub.3                                            239- 240    117          ##STR546##            H      H    ______________________________________

EXAMPLE 118

4.0 g (10 millimoles) of6-[p-(3-(4-phenylpiperid-1-yl)-propionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinonein 15 ml of ethanol were refluxed with 1.5 ml of 37% strength formalinsolution and 40 ml of 4% strength ethanolic KOH for 3 hours. Insolublematerial was filtered off under suction, after which the mother liquorwas evaporated down and the product was recrystallized from isopropanol.2.2 g of6-[p-(3-(4-phenylpiperid-1-yl)-propionylamino)-phenyl]-4-methyl-3(2H)-pyridazinonewere obtained as pale beige crystals of melting point 239°-240° C.

EXAMPLE 119

6-[p-(3-(4-Phenylpiperazin-1-yl)-propionylamino)-phenyl]-4-methyl-3(2H)-pyridazinonewas prepared from6-[p-(3-(4-phenylpiperazin-1-yl)-propionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinoneby a method similar to that described in Example 118.

The compounds of Examples 120 to 130 were obtained by reacting a6-[p-(chloro- or bromoalkanoylamino)-phenyl]-5-methyl-3(2H)-pyridazinonewith 4-phenylpiperidine or phenylpiperazine by a method similar to thatdescribed in Example 1.

    ______________________________________    Ex-    am-                                     Mp.    ple  R.sup.4R.sup.3 [x H.sub.2 O]                                 R.sup.1                                        R.sup.2                                            [°C.]    ______________________________________    120          ##STR547##             CH.sub.3                                        H    121          ##STR548##             CH.sub.3                                        H    122          ##STR549##             CH.sub.3                                        H    123          ##STR550##             CH.sub.3                                        H    124          ##STR551##             CH.sub.3                                        H    125          ##STR552##             CH.sub.3                                        H    126          ##STR553##             CH.sub.3                                        H    127          ##STR554##             CH.sub.3                                        H    128          ##STR555##             CH.sub.3                                        H    129          ##STR556##             CH.sub.3                                        H    130          ##STR557##             CH.sub.3                                        H    ______________________________________

EXAMPLE 1316-{p-[3-(4-Phenylpiperidino)-propionylamino]-phenyl}-4,5-dihydro-3(2H)-pyridazinoneA. 3-[p-(3-Chloropropionylamino)-benzoyl]-propionic acid

19.2 g (100 millimoles) of 3-(p-aminobenzoyl)-propionic acid werestirred with 24.8 g (195 millimoles) of 3-chloropropionyl chloride in200 ml of absolute acetone for 10 hours at room temperature. The mixturewas then evaporated down, the residue was stirred with 200 ml of water,and the product was filtered off under suction at 10° C., washed withcold acetone and dried at 100° C. under reduced pressure. 21 g (75%) of3-[p-(3-chloropropionylamino)-benzoyl]-propionic acid were obtained asyellowish crystals of melting point 181°-182° C. (acetonitrile).

B. 3-{p-[3-(4-Phenylpiperidino)-propionylamino]-benzoyl}-propionic acid

56 g (200 millimoles) of3-[p-(3-chloropropionylamino)-benzoyl]-propionic acid were stirred with60.7 g (440 millimoles) of potassium carbonate and 35.5 g (220millimoles) of phenylpiperidine in 900 ml of dimethylformamide for 8hours at 80° C. 2 kg of ice/water were added, after which the crystalswere filtered off under suction and recrystallized fromdimethylformamide/water, and the product was dried at 50° C. undergreatly reduced pressure. 70 g (86%) of3-{p-[3-(4-phenylpiperidino)propionylamino]-benzoyl}-propionic acid wereobtained as colorless crystals of melting point 237°-238° C.

C.6-{p-[3-(4-Phenylpiperidino)-propionylamino]-phenyl}-4,5-dihydro-3(2H)-pyridazinone

10 g (23.7 millimoles) of3-{p-[3-(4-phenylpiperidino)-propionylamino]-benzoyl}-propionic acidwere stirred with 1.2 g (23.7 millimoles) of hydrazine hydrate in 200 mlof ethanol for 5 hours at 80° C. The product was filtered off undersuction and recrystallized from dimethylformamide/water. 7.6 g (78%) of6-{p-[3-(4-phenylpiperidino)-propionylamino]-phenyl}-4,5-dihydro-3(2H)-pyridazinone.1/4H₂O were obtained as colorless crystals of melting point 238°-240° C.

The compounds of Examples 1 to 130 can be prepared similarly to Example131.

EXAMPLE 1326-{p-[3-(2-Phenylethylamino)-propionylamino]-phenyl}-4,5-dihydro-3(2H)-pyridazinone

11.18 g (40 millimoles) of6-[p-(3-chloropropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone in250 ml of ethanol were initially taken and 26.5 g (220 millimoles) of2-phenylethylamine were added dropwise, after which the mixture wasrefluxed for 6 hours. Insoluble material was filtered off, the solventwas stripped off and the mother liquor was then crystallized by addingacetone. The product was recrystallized twice from methanol to give 5.3g of6-{p-[3-(2-phenylethylamino)-propionylamino]-phenyl}-4,5-dihydro-3(2H)-pyridazinone.HClof melting point 269°-270° C.

For conversion to the free base, the hydrochloride obtained as describedabove was dissolved in methanol, and an equimolar amount of sodiummethylate was added. The solvent was stripped off and H₂ O was added,after which the substance was extracted with methylene chloride, themethylene chloride phase was dried over Na₂ SO₄, the solvent wasstripped off and the substance was stirred with acetone and thenfiltered off under suction.6-{p-[3-(2-phenylethylamino)-propionylamino]-phenyl}-4,5-dihydro-3(2H)-pyridazinoneof melting point 130°-132° C. was obtained.

    ______________________________________    Pharmaceutical examples    (A) Preparation of tablets    Composition:    ______________________________________    Active compound           10     mg    Polyvinylpyrrolidone (mean molecular                              170    mg    weight 25,000)    Polyethylene glycol (mean molecular                              14     mg    weight 4,000)    Hydroxypropylmethylcellulose                              40     mg    Talc                      4      mg    Magnesium stearate        2      mg                              240    mg    ______________________________________

The active compound is moistened with a 10% strength aqueous solution ofpolyvinylpyrrolidone and forced through a sieve of 1.0 mm mesh size, andthe granules are dried at 50° C. They are then mixed with polyethyleneglycol (mean molecular weight 4,000), hydroxypropylmethylcellulose, talcand magnesium stearate, and the mixture is pressed to give tabletsweighing 280 mg.

    ______________________________________    (B) Preparation of coated tablets:    Composition of the tablet cores:    ______________________________________    Active compound          10     mg    Lactose                  90     mg    Corn starch              60     mg    Polyvinylpyrrolidone     6      mg    Magnesium stearate       1      mg                             167    mg    ______________________________________

The active compound, lactose and corn starch are mixed, moistened withan 8% strength aqueous solution of the polyvinylpyrrolidone, andgranulated by passing through a sieve of 1.5 mm mesh size. The granulesare dried at 50° C. and forced through a 1.0 mm sieve. The granules thusobtained are mixed with magnesium stearate, and the mixture is pressedto form tablet cores. These are coated in a conventional manner with ashell consisting essentially of sugar and talc.

We claim:
 1. A 6-(alkanoylaminoaryl)-3(2H)-pyridazinone derivative ofthe formula I ##STR558## wherein the substituents on the phenyleneradical are para to one another, A and B are each hydrogen or togetherform a bond, R¹ is hydrogen or methyl, R² is hydrogen or, where A and Bare each hydrogen R¹ and R² together form a C₁ -C₂ -alkylene radical, R³is a straight-chain C₁ -C₄ -alkylene group which can be substituted byC₁ -C₃ -alkyl group or by two methyl groups, and R⁴ is(b) a group of theformula II ##STR559## where the broken line can be an additional bond,R⁵ is C₁ -C₄ -alkyl which is unsubstituted or substituted by phenyl, orphenyl which is unsubstituted or substituted by 1 or 2 halogen atoms, oris a group of the formula R⁷ R⁸ N, where R⁷ is hydrogen or phenyl, andR⁸ is C₁ -C₄ -acyl or benzoyl, or R⁷ and R⁸, together with the nitrogenatom, form a benzimidazol-2-on-1-yl group, R⁶ is C₁ -C₄ -alkyl,hydroxyl, C₁ -C₄ -acyl, (C₁ -C₅ -alkoxy)-carbonyl or cyano, or R⁵ and R⁶together form a C₁ -C₄ -alkylene chain, and m is 0, 1 or 2, or (c) agroup of the formula III ##STR560## `where R⁹ is a C₁ -C₃ -hydrocarbonradical which may be substituted by phenyl or a C₃ -C₈ -cycloalkyl (inwhich case a C₅ -C₈ -cycloalkyl group can be benzofused) or C₆ -C₁₀-aryl which can contain 1 to 3 C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy,trifluoromethyl, nitro, hydroxyl, C₁ -C₄ -acyl, carboxyl, (C₁ -C₅-alkoxy)-carbonyl, amido, N-(C₁ -C₄ -alkyl)amido, N,N-di-(C₁ -C₄-alkyl)amido, tri(C₁ -C₄ -alkyl)-silyl, cyano, amino, C₁ -C₄-alkylamino, di-(C₁ -C₄ -alkyl)amino, C₁ -C₄ -alkanoyl amino groupsand/or halogen atoms; a C₆ -C₁₀ -aroyl group which is unsubstituted orsubstituted by 1 to 3 C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, trifluoromethyl,nitro, hydroxyl, C₁ -C₄ -alkanoyl, carboxyl, C₁ -C₅ -alkoxy-carbonyl,N,N-di-(C₁ -C₄ -alkyl)-amido, cyano, di-(C₁ -C₄ -alkyl)-amino groupsand/or halogen atoms; or a hetaroyl group having 5 to 6 ring members,which can contain 1 to 3 hetero atoms and may be benzofused; a C₃ -C₁₂-cycloalkyl, C₁ -C₈ -acyl or (C₁ -C₅ -alkoxy)-carbonyl group or a C₆-C₁₀ -aryl radical which is unsubstituted or monosubstituted,disubstituted or trisubstituted by halogen, C₁ -C₄ -alkyl, C₁ -C₄-alkoxy, hydroxyl, trifluoromethyl, C₁ -C₄ -acyl, carboxyl, (C₁ -C₅-alkoxy)-carbonyl, cyano, nitro, amino, C₁ -C₄ -alkylamino, di-C₁ -C₄-alkylamino, arylamino or C₁ -C₄ -acylamino; or a 5-membered or6-membered hetaryl radical which may be benzofused, contains 1 to 3nitrogen atoms and may or may not contain an oxygen atom or sulfur atom,and p is 2 or 3, or (e) a group of the formula V ##STR561## where R¹²and R¹³ are each hydrogen, halogen, C₁ -C₄ -alkyl or C₁ -C₄ -alkoxy, andn is 1, 2, or
 3. 2.6-{p-[3-(4-Phenyl-1-piperazino)-propionylamino]-phenyl}-5-methyl-4,5-dihydro-3(2H)-pyridazinone.3.6-{p-[3-(4-Pyrid-2-yl-1-piperazino)-propionyl-amino]-phenyl}-5-methyl-4,5-dihydro-3(2H)-pyridazinone.4.6-{p-[3-(4-Benzyl-1-piperazino)-propionylamino]-phenyl}-5-methyl-4,5-dihydro-3(2H)-pyridazinone.5.6-{p-[2-(4-Phenyl-1-piperidino)-acetylamino]-phenyl}-5-methyl-4,5-dihydro-3(2H)-pyridazinone.6.6-{p-[3-(4-Phenyl-1-piperidino)-propionylamino]-phenyl}-4,5-dihydropyridazinone.7.6-{p-[3-(4-Phenyl-1-piperidino)-propionylamino]-phenyl}-5-methyl-4,5-dihydropyridazinone.8.2-{p-[3-(4-Phenyl-1-piperidino)-propynylamino]-phenyl}-3,4-diazabicyclo[4.1.0]hept-2-en-5-one.9.6-{p-[3-(4-Phenyl-1-(1,2,3,6-tetrahydropyridino)-propionylamino]-phenyl}-5-methyl-4,5-dihydro-3(2H)-pyridazinone.10.6-{p-[3-(4-Phenyl-1-piperidino)-propionylamino]-phenyl}-3(2H)-pyridazinone.11.6-{p-[3-(1-(1,2,3,4-Tetrahydroisoquinolino)propionylamino]-phenyl}-5-methyl-4,5-dihydro-3(2H)-pyridazinone.12. A therapeutic composition comprising a pharmaceutical excipient andan effective amount of a 6-(alkanoyl-aminoaryl)-3(2H)-pyridazinonederivative as claimed in claim 16 as the active compound.
 13. The methodof treating disease caused by thrombocyte aggregation in a patientsuffering therefrom which comprises administering an effective amount ofa 6-(alkanoyl-aminoaryl)-3(2H)-pyridazinone derivative as claimed inclaim 12.